Macrophage Recycling of Red Blood Cells and Iron Following Transfusion

Red blood cells (RBCs) destined for transfusion can be refrigerator stored for up to 42 days prior to transfusion. During this ex vivo storage period, RBCs are progressively damaged in a process that is termed the RBC storage lesion. The end result of this storage lesion is that with longer durations of storage prior to transfusion, an increased number of storage-damaged RBCs are cleared from the circulation via extravascular hemolysis. Studies in mice, dogs, and humans suggest that transfusion of older, stored RBCs, but not fresh RBCs, produce acute elevations in circulating markers of extravascular hemolysis (e.g., indirect bilirubin and transferrin saturation). Furthermore, hepcidin is induced in humans approximately 4-6 hours after transfusion and likely results in the return to baseline serum iron levels by 20-hours following transfusion. This is associated with a concomitant rise in serum ferritin levels, suggesting that hepcidin-induced degradation of ferroportin results in intracellular storage of iron within macrophages. Furthermore, the rate at which the macrophages release iron can be greater than the capacity of circulating transferrin to handle that iron, resulting in production of non-transferrin-bound iron. This pathogenic form of iron may be a cause of adverse effects in transfusion recipients. Indeed, in animal models, iron availability is associated with increased morbidity and mortality from infectious challenges with certain bacteria. A human study comparing transfusion of a single unit of RBCs following 1, 2, 3, 4, 5, or 6 weeks of storage suggests that the RBC storage lesion does not develop linearly and is only capable of inducing non-transferrin-bound iron production in healthy adult recipients following 5-6 weeks of storage. However, this relationship may differ in critically-ill populations. Furthermore, there is significant variability among blood donors in their RBC quality following storage. There are likely to be both genetic and environmental causes to this variability. Some of these causes may be donor glucose-6-phosphate dehydrogenase status, iron status, and/or dietary lipid content. In addition, in animal models, the clearance of a bolus of storage-damaged RBCs is associated with a pro-inflammatory cytokine response. Although this has yet to be demonstrated in studies using healthy adult human volunteers, studies in pediatric patient populations suggest that RBC transfusions may be associated with a pro-inflammatory response in this vulnerable population. The precise mechanism of inflammation following transfusion, and its clinical implications, has yet to be resolved. Finally, recent randomized clinical trials suggest that there are no clinical outcome differences when patients are randomized to receiving transfusions of fresh RBCs as opposed to the standard of care. Perhaps the RBC storage lesion has no clinical consequences to the transfusion recipient. However, these studies were not powered nor designed to test the effects of transfusion of RBCs during the final week of storage, in which studies suggest the effects would be most striking. Furthermore, many of the recipients in these studies already suffered from baseline hemolysis (e.g., from cardiac pump induced hemolysis, malaria, and sickle cell disease). It is unlikely that the added hemolysis from a transfusion of older RBCs would have a clinical impact given the level of baseline hemolysis from other causes observed in these patient populations. Thus, whether there are pathophysiologic consequences to the clearance of storage-damaged RBCs is still debatable.